Antibacterial compositions and methods

ABSTRACT

Imines of 2-formylquinoxaline-3-carboxylic acid-1,4-dioxides and their salts are obtained through treatment of the lactone or a salt of 2-dihydroxymethylquinoxaline-N,N-dioxide-3-carboxylic acid with a reactant bearing a free primary amino group. The resultant compounds and their non-toxic salts are antibacterial agents and can be incorporated in pharmaceutical compositions and feedstuffs for this use. A typical embodiment is 2(carbomethoxyhydrazonomethyl)-quinoxaline-3-carboxylic acid-1,4dioxide.

United States Patent Seng et al. 1 Jan. 14, 1975 ANTIBACTERIALCOMPOSITIONS AND [56] References Cited METHODS UNITED STATES PATENTS[75] Inventors: Florin Seng,Cologne-Buchheim; 3,371,090 2/1968 Johnston260/2406 Kurt Ley, Odenthal-Globusch; Karl Georg Metzger, FOREIGNPATENTS OR .APPLICATIONS wuppertapglberfeld, a f 1,215,815 12/1970 GreatBntam 260/250 R Germany P E -J e D. Goldb [73] Assignee: BayerAktiengesellschaft, Hmary xammer erg Leverkusen, Germany ABSTRACT [22]Flled: 201973 Imines of 2-formylquinoxaline-3-carboxylic' acid-1,4- [21]Appl. No.: 389,886 dioxides and their salts are obtained throughtreatment of the lactone or a salt of 2- Related Apphcatmn Datadihydroxymethylquinoxaline-N,N-dioxide-3'carboxylic [62] pivisronof Ser.No. 323,953,Jan. 15, 1973, wh acid with a reactant bearing a freeprimary amino a of 130907 March 1971' group, The resultant compounds andtheir non-toxic salts are antibacterial agents and can be incorporated[30] Forelgn Apphcatmn Pnonty Data in pharmaceutical compositions andfeedstuffs for this Apr. 2, 1970 Germany 2105676 use. A typicalembodiment is 2-(carbomethoxyhydrazonomethyl)-quinoxaline3-carboxylicacid-l ,4- [52] US. Cl. 424/250 i [51] Int. Cl A61k 27/00 [58] Field ofSearch 424/250 30 Claims, No Drawings ANTIBACTERIAL COMPOSITIONS ANDMETHODS i COOY wherein Y is hydrogen, an alkali metal cation or thecation 5 G) R -NH and each of R and R 'is identical to or different fromthe other and is selected from the group consisting of 21. alkyl,substituted alkyl or cycloalkyl; b.

in which each of R and R when taken independently is identical to ordifferent from the other, and is selected from the group consisting ofhydrogen, alkyl or substituted alkyl, or when R and R are taken togetherwith the nitrogen atom to which they are attached a 5- to 7-memberedheterocyclic ring optionally containing as a ring member oxygen,sulphur, S or N-alkyl;

-u -N i in which X is O, S or NH and, R and R are as above defined;

ids,

in which R is alkyl or substituted alkyl;

in which R is phenyl, pyridyl or norhornyl, and X is as defined above;

in which R, R and X are defined above; or

A preferred group of the imines and salts of the invention are those ofthe above general formula 1 in which:

Y has the meanings given above;

each of R and R is identical to or different from the other and isselected from the group consisting of a. alkyl or hydroxyalkyl of from 1to 4 carbon atoms or a 6-membered or 7-membered monocycloorbi-eycloalkyl group; b.

in which each of R and R when taken independently is identical to ordifferent from the other and is selected from the group consisting ofhydrogen, alkyl or hydroxyalkyl of from 1 to 4 carbon atoms, or when Rand R are taken together with the nitrogen atom to which they areattached, a o-membered heterocyclic ring optionally containing as a ringmember oxygen or S0 -Nl-l i-N in which X is O, S or NH, and R and R areas herein defined; d.

in which R is alkyl or hydroxyalkyl of from 1 to 4 carbon atoms; and

in which R is phenyl, pyridyl or norbornyl, and X is as herein defined.

Alphatic groups embraced by R and R include straight-chain or branchedalkyl groups of from 1 to 6, preferably 1 to 4, carbon atoms.Cycloaliphatic radicals contain from 3 to 7, preferably 5 to 7, carbonatoms and include both monocyclic and bicyelic ring systems.

These aliphatic or cycloaliphatic groups can be optionally substituted,for example, by hydroxy, alkoxy, or acyloxy, the alkoxy and acyloxygroups containing 1 to 4, preferably 1 or 2, carbon atoms. The hydroxygroup is the preferred substituent. Typical aliphatic and cycloaliphaticgroups thus include methyl, ethyl, npropyl, isopropyl, n-butyl,isobutyl, tert.-butyl, npentyl, isopentyl, hexyl, 2-hydroxyethyl,cyclopropyl, cyclopentyl, cyclohexyl, bicyclo-(2,2,l)-heptyl(norbornyl), and the like.

The substituents R and R are hydrogen or alkyl of from 1 to 4,preferably 1 or 2, carbon atoms. These alkyl groups can be optionallysubstituted with hydroxy, alkoxy or acyloxy, alkoxy and acyloxy groupscontaining 1 to 4, preferably 1 or 2, carbon atoms. Thus included areethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert.-butyl, as wellas the corresponding groups substituted by hydroxy.

R and R when taken together with the nitrogen atom to which they areattached, can also form a heterocyclic ring, preferably containing sixring members, and preferably with an oxygen atom, a sulphur atom, anN-alkyl group containing 1 to 4, preferably 1 or 2, carbon atoms, or theS group, as a ring member in the p-position relative to the nitrogenatom to which R and R are attached.

R is an alkyl of from 1 to 4, preferably 1 or 2, carbon atoms which mayalso be optionally substituted by hydroxy, alkoxy, acyloxy, alkoxy andacyloxy and containing l to 4, preferably 1 or 2, carbon atoms. Thehydroxy group is a particularly preferred substituent. R thus embracessuch groups as methyl, ethyl, 2- hydroxyethyl and the like.

The alkali metal cation Y is, for example, that of sodium or potassium,preferably that of sodium.

R is phenyl, pyridyl or norborn-Z-yl. When R is pyridyl, it can bebonded in the 2-, 3- or 4-position relative to the pyridyl nitrogenatom.

The above class of imines are obtained according to the process of thepresent invention by treatment of lox0-3-hydroxy-l ,3-dihydro-furo-( 3,4,-b)-quinoxaline- 4,9-dioxide, which has the formulaz (I s iu ii a ora salt thereof of the formula OH 0 Q with an amine of the generalformula H NR, in which R is as previously defined, M is an alkali metalor alkaline earth metal cation and x is l or 2.

The salts of the formula can be obtained from thc lactone of formulathrough treatment with alkali metal or alkaline earth metal hydrogencarbonates.

M is preferably the cation of sodium, potassium or most preferablycalcium.

Both inorganic and organic polar solvents can be used as diluents forthe reaction according to the invention, such as for example water,lower aliphatic alcohols of l to 4 carbon atoms, lower aliphaticnitriles such as acetonitrile, tetrahydrofurane, dioxane,dimethoxyethane, pyridine, dimethyl-formamide and the like.

The reaction according to the invention is carried out at a temperatureof about 0C to about 50C, preferably 20C to about 35C. I

In practice, the lactone or lactone salts are dissolved or suspended inthe diluent, and this solution or suspension is then treated with anappropriate quantity of the amine. The formation of the imine or of theimine salt takes place in a weakly exothermic reaction and the finalproduct is then isolated through conventional methods.

The imine salts l can also be prepared by the reaction of the free acidswith amines.

The salts may be obtained in a subsequent step by conventionaltechniques or directly in the reaction of the lactone with the amine. Ifabout 2 mols ofthc amine per mol oflactone are employed, the productwill be in the form of that amine salt. If an alkali metal salt oralkaline earth metal salt of the lactone is employed, or if it isdesired to obtain the free acid from the lactone,

only about 1 mol of the amine per mol of the lactone The followingexamples will serve to further typify the nature of this inventionwithout being a limitation on the scope thereof.

EXAMPLE 1 23.4 g (0.1 mol) of 1-oxo-3-hydroxy-1,3-dihydrofuro-(3,4-b)-quinoxaline-4,9-dioxide are suspended in 60 ml ofwater and G (0.2 mol) of 60% strength aqueous isopropylamine solutionare added. The temperature is kept below C by slight cooling. After afew minutes, a clear solution is produced. Evaporation in vacuo yields45 g of the compound of the formula COOH H in the form of yellowcrystals, which after recrystallisation from isopropanol melt at l2325C,with decomposition.

Analysis: C H N.,O (molecular weight 334):

Calculated: C, 57.5%; H. 6.6% N 16.8%. Found: (1.571%; H, 5.8%; N 16.8%.

EXAMPLE 2 27.4 g (0.1 mol) of the Na salt of2-(dihydroxymethyl)-3-carboxylic acid-quinoxaline-di-N- oxide aredissolved in ml of water and 7.3 g (0.1 mol) of tert.-butylamine areadded. The temperature is kept at 25C by cooling. After 1 hour, thesolution is 1.. n cihumn-comu 1:

N OONa CH= -CH evaporated in vacuo and 32 g of the compound of the CQONaformula I CH: '-CH are obtained in the form of yellow crystals whichafter recrystallisation from acetonitrile/water melt at 228C, withdecomposition.

Analysis: C l'l N NaQ, (molecular weight 311):

Calculated: C, 54.0%; H, 4.5%; N, 13.5%: Na 7.4%.

Found: C.5317%; H, 4.9%; N, 13.5%; Na 6.9%.

The 1-oxo-3-hydroxy-1 ,3-dihydro-furo( 3 ,4-b)- quinoxaline-4,9-dioxideof the formula (I) required as the starting compound can be obtained asfollows:

30.7 g (0.1 mol) of 2-bismethoxy-methy1-3-dimethylaminocarbonyl-quinoxaline-1,4-di-N-oxide are introduced into 100ml of 10% strength aqueous hydrochloric acid. A clear solution results.and after a short time the compound according to the invention separatesout in the form of a yellow precipitate. which is filtered off after 6hours. 17 g (72.6% of theory) of 1-oxo-3-hydroxyl ,3-dihydro-furo-(3,4-b)-quinoxaline-4,9-dioxide are thus obtained in the form of yellowcrystals.

The compound is purified by dissolving it in sodium bicarbonatesolution, filtering and acidifying the filtrate. The purified compoundmelts at 156-159C, whilst foaming.

The lactone (9) is suspended in water and approxi Analysis: C,.,H N,O(235): mately the stoichiometrically required amount of the C'll': .37;2.7; i, ,4 t; g z f' 25 g 5 alkali metal hydrogen carbonate or alkalineearth metal hydrogen carbonate 18 added at room temperature. The 5 saltof the lactone (10), thus produced, precipitates, t after evaporation ofthe solution if necessary, and can The alkali metal salts oralkaline-earth metal salts of be isolated in the usual manner.l-oxo-3-hydroxy-l,3-dihydro-furo (3,4-b) quinoxa- The following areobtained analogously to Examples line-4,9-dioxide can be manufactured asfollows: 1 d 2;

Ekample MeItingPoint (C) No. v Compound (decomposition) 0O 6 H N-Cl'liii 3 3 N H=N-CH ooa u-c a I N crew-c a 6 GD GE E 3 138- 40 COOl-l N 'CH1 3 l 3 CH3 f CH=N {CR Continued Example- Melting Point (C) No. Compound(decomposition) \ICOOH3NCH2- CH2-QH y l CH:NCH-2CHOH I COOH COONa v YOOH N-NH 3 2 q CH::N -NH -C0ntinued Example Melting Point (C) N Compound(decomposition) I 00m (I (If H=N-NH 0ca c11 0n j:COONa CR==NNHCO /NCOONa As has already been mentioned, the new compounds of the inventionsurprisingly show an excellent chemotherapeutic activity. Theirchemotherapeutic action was examined both in animal experiments (oraland TABLE 2 Minimum inhibitory concentration (MIC) in 'y/ml of medlum,measured by the series dilution test (complete medium), incubationtemperature: 37C, determinasubcutaneous adm nlstratlon) with acutebacterlal lntion f the MIC after 18 24 and 48 hours fectlons, and 1nvltro. In both cases the compounds show a very good antibacterialaction, and the range of Compound or action encompasses bothGram-negative and Gram- Bwerum Example positive bacteria. Thechemotherapeutic activity of the Smpwmcm faewlis ATCC 9700 50 compoundsaccording to the lnventlon permlts their do. go. go. 120 do. 0. o. .0use ln human medlclne and in veterinary medlclne. do do 8698 )0Furthermore, the compounds can be employed as feeddo. do. do. 8699 100do. do. do. 8711 50 stuff addltlves, especially in rals lng younganimals or smpmwcms film: ATCC a H '00 fatstock. The good in vltro and mvlvo activity of the do, Bkmhke compounds according to the invention canbe seen 13 r 25 f T l 2 3 b 1 do. do. do. species 100 rom ab es 1. and eowdo. do. do. liquef. so

The mlnlmum lnhlbltory concentratlons ln vltro for o I dov gsome of thenew compounds shown in Table 1 (MIC) fg 2 25150 were determined by theplate test in an agar medium of do. do. 55 B 5 34 u do. do. 14 1225 thefollowing composition. A 26] .1540

do. do. 183/58 6-12 Proteus mirabl'lis G 12 do. do. 2935 12 proteosepeptone 10.0 g per lltre veal extract (solids) 10.0 g do. do. vulgar3400 50 dextrose 2.0 g do. do. H7 17 Sodium fluoride 3 g do 5Pseudomorlas uerugmusu W 400 do. do. M dlsodlum phosphate 20 g do. do.do do B vs sodium acetate 1.0 g do. do. adenine sulphate (1.01 g do. do.KIM-"6" 1003' guanine hydrochloride 0.01 g do. do. g 61 uracil 0.01 gdo. do. Salmonella paralyphll BB II xamhm g (10' Curynebacteriumdiphleriae gravir 5-10 neutral agar g Staphylococcus uureus 133 I; do. Ido. 7705 2 5.10 X 10 germs were inoculated per plate. N do I 1 1311/4]BRL l2 l Read ngs were taken after 24 and 48 hours, and the lnz 'f 'icubatlon temperature was about 37C. Mycoplarma galliseplit'um*) oMycopluxma granulartxm") 3 Table l Mycobaclerl'um tuherculmis H 37 RV)mcasured in a PPLO medium MIC in 'y/ml of medium Compound of Compoundof Compound of Bacterium Example 10 Example 12 Example l3 For thecompound of Example 3, the followlng mini- 40 mal inhibitoryconcentratlons (MIC) (y/ml of nutrlent flfli li z i 20 medium) weremeasured by the series dllutlon test Escherichia (PPLO medium),incubation temperature 37C, deter- C 165 50 mination after 18, 24 and 48hours. Proteus vulgaris species 150 10 Pseudomonas aeruginosa BacteriumMIC Bonn 100 100 pseudPmonas Mycnplasma gullisepliz'um 1(10 """EMycoplasmu grunularum 25 [\Zalteru 100 Mycuplasmu huvirhl'nix 200pneumonia 63 100 50 KlewrieI/H In anlmal experiments on mice, theeffectlve 100% 0 5 2 dose (ED ln mg/ Kg was determlnedfor certamcomaureus 133 10 pounds of the mventlon after lntraperltoneal lnfectlonand subcutaneous (s.c.) or oral (p.o) adminlstratlon of Pyogew W thepreparation Table 3 Compound of Compound of Compound of Compound ofExample 3 Example 8 Example 13 Example 14 Bacterium s.c. p.c. s.c. p.c.sLc. p.c. s.c. p.c.

Escherichia 50 S0 100 25 25 50 100 call C Slaphylacoc- 25 50 CIAS aureuxIn general, it has proved advantageous, in acute general infections, toadminister amounts of about mg to about 200 mg per kilogram, preferablyabout 25 to about 50 mg per kilogram of body weight per day, to achieveeffective results. Nevertheless it can at times be necessary to deviatefrom the amounts mentioned, in particular depending on the body weightof the test animal or patient or on the nature of the method ofadministration, but also because of the type of animal and itsindividual behaviour towards the medicament, or because of the nature ofthe formulation of the latter, and the point in time or interval atwhich administration takes place. Thus it can, in some cases, suffice touse less than the abovementioned minimum amount, whilst in other casesthe upper limit mentioned must be exceeded. In the case of theadministration of larger amounts it can be advisable to divide theseinto several individual doses over the course of the day. The same rangeof dosages is envisaged for administration in human medicine. The othercomments made above also apply in a general sense.

Accordingly, the present invention provides a pharmaceutical compositioncontaining as an active ingredient at least one of the new compounds ofthe general formula (1) given above in admixture with a pharmaceuticallyacceptable solid or liquid diluent or carrier as hereinafter defined.

In the present specification the expression pharmaceutically acceptablediluent or carrier means a nontoxic substance that when mixed with theactive ingredient or ingredients renders it suitable for administration.The expression preferably excludes water and low-molecular weightorganic solvents commonly used in chemical synthesis, except in thepresence of other pharmaceutically necessary ingredients such as saltsin correct quantities to render the composition isotonic, buffers,surfactants, colouring and flavouring agents, and preservatives.Examples of suitable liquid diluents and carriers are vegetable oils,glycerol, propylene glycol, polyols, buffered aqueous solutions,isotonic saline aqueous solutions, syrups and lotion bases. Examples ofsuitable solid diluents and carriers are starches, cellulose and itsderivatives, sugars, stearates and stearic acid, talc, and ointmentbases. Examples of pharmaceutical compositions according to theinvention are ointments, pastes, creams, sprays, lotions, aqueous andnon-aqueous suspensions, emulsions, and solutions (includingparenterally injectable solutions), elixirs and syrups, and granulatesand powders either free-flowing or compressed into tablets.

Pharmaceutical compositions of the invention adapted for oraladministration are a preferred embodiment of the invention. The diluentsand carriers used are preferably therefore those that adapt the activeingredient or ingredients for oral administration. Examples of suchdiluents and carriers are solid vehicles, excipients and lubricants suchas glucose, lactose and sucrose, corn and potato starch, sodiumcarboxymethylcellulose, ethyl cellulose and cellulose acetate, powderedgum tragacanth, gelatin, alginic acid, agar, talc, stearic acid andsodium, calcium and magnesium stearates, sodium lauryl sulphate,polyvinyl-pyrrolidone, sodium citrate, calcium carbonate, and dicalciumphosphate.

The pharmaceutical compositions of the invention may also contain othernon-toxic adjuvants and modifiers such as dyes, surfactants, perfumes,flavouring agents, such as sweeteners, preservatives and biocides.

Pharmaceutical compositions of the invention adapted for parenteralinjection are another preferred embodiment of the invention. Thediluents and carriers used are therefore preferably those that adapt theactive ingredient for parenteral administration. Examples of diluentsand carriers that adapt the active ingredient for parenteraladministration are solvents and suspending diluents such as water,vegetable fatty oils, such as sesame oil, groundnut oil, corn oil, andcottonseed oil, aqueous propylene glycol, N,N-di-methylformamide, anddimethyl sulphoxide. In general, any non-aqueous diluent can be usedthat does not reduce the activity of the active ingredient andis-non-toxic in the dose em ployed.

For the administration of the water-soluble compounds of the inventionby parenteral injection sterile aqueous solutions can be employed, andare within the scope of the pharmaceutical compositions of theinvention. Such aqueous solutions should preferably when necessary bebuffered in the usual manner, and the liquid diluent should preferablybefore administration be rendered isotonic by adding the requisiteamount of salt or glucose. Such sterile buffered isotonic solutions areespecially suitable for intravenous, intramuscular and intraperitonealinjections. These pharmaceutical compositions of the invention canfurther contain local anaesthetics or substances that promote thediffusion I of the active ingredient, for example hyaluronidase.

The pharmaceutical compositions of the invention preferably contain 0.5to wt.% of at least one new compound of the invention.

The present invention also provides medicaments in dosage unit form ashereinafter defined comprising as an active ingredient at least onecompound'of general formula (1) given above either along or in admixturewith a pharmaceutically acceptable solid or liquid diluent or carrier.In this case the diluent or carrier is preferably as defined above butcan also be water or another common solvent.

The expression medicament in dosage unit form" used in the presentspecification means a medicament in the form of discrete portions eachcontaining a unit dose or a multiple or sub-multiple of a unit dose ofthe active ingredients(s); for example, one, two, three or four unitdoses or a half, a third or a quarter of a unit dose. A unit dose" isthe amount of the active ingredient(s) to be administered on oneoccasion and will usually be a daily dose, or for example a half, athird, or a quarter of a daily dose depending on whether the medicamentis to be administered once or, for example, twice, 3 times, or 4 times aday.

The discrete portions constituting the medicament in dosage unit formcan include a protective envelope. The active ingredient can beundiluted and contained in such an envelope, or can be mixed with apharmaceutically acceptable solid or liquid diluent or carrier asdefined above. Such portions can for example be in monolithic coherentform, such as tablets, lozenges, pastilles, pills, suppositories, ordragees; in wrapped or concealed form, the active ingredients beingwithin a protective envelope, such as wrapped powders, cachets, sachets,capsules, or ampoules; or in the form of a sterile solution suitable forparenteral injection, such as ampoules of buffered, isotonic, sterile,pyrogenfree aqueous solution; or in any other form known in the art.

As stated above, peroral administration is a preferred mode ofadministration. Preferred medicaments in dosage unit form according tothe invention are therefore those adapted for oral administration, suchas tablets, pills, dragees, capsules, and cachets, as well as wrappedpowders containing the active ingredient in powdered form with apowdered diluent or carrier for suspension in water before being taken.

As also stated above a further preferred mode of administration isparenteral administration. Preferred medicaments in dosage unit formaccording to the invention are therefore those adapted for parenteraliniection, such as ampoules containing a measured quantity of a sterileisotonic saline injectable aqueous solution of the new activeingredient, which may be buffered with a pharmaceutically acceptablebuffer and are preferably free of pyrogens.

' The preferred unit dose for administration of the medicaments of theinvention is 250-16000 mg. of active ingredient, preferably 1250-4000mg. This will usually be administered once daily.

The invention further provides a method of combatting bacterialinfection in an animal which comprises administering to the animal(preferably parenterally or perorally) an effective amount of one of thenew compounds, either alone, as a pharmaceutical composition accordingto the invention, or as a medicament in dosage unit form according tothe invention.

Indications envisaged in human medicine are espe cially generalinfections, and infections of the efferent urinary tract, caused byGram-positive and Gramnegative bacteria and by mycoplasma, and inveterinary medicine are general infections caused by Gramnegative andGram-positive bacteria and my mycoplasma. Infections of the respiratorypassages in poultry, especially in chicks, and mastitis of cows, may bementioned particularly.

The new compounds can, as has already been mentioned, also be employedas a feedstuff additive, predominantly in raising young animals,especially chicks and fatstock.

The preparations can be administered in the feedstuff, special feedstuffpreparations and feedstuff concentrates, but also via the drinkingwater.

The invention therefore also provides animal feedstuffs and feedstuffconcentrates containing at least one of the new compounds of generalformula (1).

The administration of the new compounds together with the feedstuff orfeedstuff preparations and/or with the drinking water makes it possibleto prevent or treat infections by both Gram-negative and Gram-positivebacteria and mycoplasma, and can furthermore contribute to betterutilization of the feedstuff. As examples of frequently occurringveterinary illnesses which cause considerable economic damage and whichcan 1 be prevented or treated by administering the new com- N OOY iCH==N-R 0 or a pharmaceutically acceptable nontoxic salt thereof whereinY is hydrogen, an alkali metal cation or the cation 5 G) R"'- -'NH andeach of R and R is NTI! wherein X is O, S or NH and R is phenyl, pyridylor norbornyl, in combination with a pharmaceutically acceptablenon-toxic inert diluent or carrier. 2. An antibacterial compositionaccording to claim 1 wherein X is O.

3. An antibacterial composition according to claim 1 wherein X is S.

4. An antibacterial composition according to claim 1 wherein X is NH..5. An antibacterial composition according to claim 1 wherein R isphenyl.

6. An antibacterial composition according to claim 1 wherein R ispyridyl.

7. An antibacterial composition according to claim I wherein R isnorbornyl.

8. An antibacterial composition according to claim 1 wherein Y ishydrogen.

9. An antibacterial composition according to claim wherein Y is a sodiumor potassium cation.

10. An antibacterial composition according to claim 1 in oraladministration form.

11. An antibacterial composition according to claim 1 in subcutaneousadministration form.

12. An antibacterial composition according to claim 1 wherein thecompound is csmz-sa-Co Q 19. A method according to claim 16 wherein X isNH.

- N OONa 20. A method according to claim 16 wherein R is l 14. Anantibacterial composition according to claim 1 wherein the compound is15. An antibacterial composition according to claim 1 wherein thecompound is 4 OCNa 16. A method of treating bacterial infections inhumans and animals which comprises administering to said human or animalan antibacterially effective WTICUCX a \1; cane-am-cd-Gu 28. A methodaccording to claim 16 wherein the compound is amount of a compound ofthe formula if 0;, e ite or a pharmaceutically acceptable non-toxic saltthereof wherein 0 Y is hydrogen, an alkali metal cation or the cation@[NjiMma 29. A method according to claim 16 wherein the compound isCOObia 55 30. A method according to claim 16 wherein the compound is andEach of R and R is X is O, S or NH and R is phenyl, pyridyl ornorbornyl, in combination with a pharmaceutically acceptable non-toxic65 inert diluent or carrier. 17. A method according to claim 16 whereinX is 0. 18. A method according to claim 16 wherein X is S.

2. An antibacterial composition according to claim 1 wherein X is O. 3.An antibacterial composition according to claim 1 wherein X is S.
 4. Anantibacterial composition according to claim 1 wherein X is NH.
 5. Anantibacterial composition according to claim 1 wherein R4 is phenyl. 6.An antibacterial composition according to claim 1 wherein R4 is pyridyl.7. An antibacterial composition according to claim 1 wherein R4 isnorbornyl.
 8. An antibacterial composition according to claim 1 whereinY is hydrogen.
 9. An antibacterial composition according to claim 1wherein Y is a sodium or potassium cation.
 10. An antibacterialcomposition according to claim 1 in oral administration form.
 11. Anantibacterial composition according to claim 1 in subcutaneousadministration form.
 12. An antibacterial composition according to claim1 wherein the compound is
 13. An antibacterial composition according toclaim 1 wherein the compound is
 14. An antibacterial compositionaccording to claim 1 wherein the compound is
 15. An antibacterialcomposition according to claim 1 wherein the compound is
 16. A method oftreating bacterial infections in humans and animals which comprisesadministering to said human or animal an antibacterially effectiveamount of a compound of the formula
 17. A method according to claim 16wherein X is O.
 18. A method according to claim 16 wherein X is S.
 19. Amethod according to claim 16 wherein X is NH.
 20. A method according toclaim 16 wherein R4 is phenyl.
 21. A method according to claim 16wherein R4 is pyridyl.
 22. A method according to claim 16 wherein R4 isnorbornyl.
 23. A method according to claim 16 wherein Y is hydrogen. 24.A method according to claim 16 wherein Y is a sodium or potassiumcation.
 25. A method according to claim 16 wherein the administration isoral.
 26. A method according to claim 16 wherein the administration isby subcutaneous injection.
 27. A method according to claim 16 whereinthe compound is
 28. A method according to claim 16 wherein the compoundis
 29. A method according to claim 16 wherein the compound is
 30. Amethod according to claim 16 wherein the compound is